tbuckley/cabot-search huggingface dataset:
Abstract 14652: Inherited Genetic Variants in Inflammatory Genes Modulate the Increased Mortality Risk in Patients With HFrEF and Clonal Hematopoiesis
Authors: Sebastian Cremer, Nikoletta Katsaouni, Wesley Abplanalp, Alexander Berkowitsch, Klara Kirschbaum, Michael Rieger, Steffen Rapp, Philipp Wild, Stefanie Dimmeler, Marcel Schulz, Andreas M Zeiher
Journal: Circulation (2022)

Aims: Clonal hematopoiesis (CH) was shown to be associated with increased mortality in patients with ischemic heart failure with reduced ejection fraction (HFrEF). Mechanistically, circulating monocytes of mutation carriers display increased expression of proinflammatory genes. Inherited genetic variants (SNP) in the IL-6 pathway are well known to affect inflammatory activation. Therefore, we investigated whether known SNPs in genes encoding for components of the inflammasome/IL-6 signaling pathway modulate fatal outcomes in HFrEF patients with CH. Methods and Results: In a total of 446 patients with chronic HFrEF, blood or bone marrow cells were analyzed for the CH mutations DNMT3A and TET2 as well as 48 preselected SNPs affecting genes in the NLRP3 inflammasome/IL-6 signaling pathway. The 103 patients carrying a CH driver mutation demonstrated significantly increased mortality compared to the 343 patients without CH mutations (p=0.0064). We identified three commonly occurring variants known to disrupt IL-6 signaling (rs2228145, rs4129267 and rs4537545), which abrogated the increased mortality risk in patients with HFrEF and CH (p≤0.05 for each SNP). On the contrary, three different SNPs (rs2250417, which is associated with increased IL-18 levels; rs4722172 and rs4845625, which are known to activate IL-6 signaling) were identified to mediate fatal outcomes in patients with HFrEF and CH (p&lt;0.05 for each). sc RNA-sequencing of circulating monocytes of patients with HFrEF revealed increased inflammatory signaling in DNMT3A mutation carriers harboring IL6/IL18 activating SNPs. Conclusion: Inherited variants in loci encoding for genes involved in inflammatory signaling interact with mortality risk in HFrEF. These data provide mechanistic insights into inflammatory mechanisms contributing to fatal outcomes of HFrEF in CH carriers, but may also inform trials evaluating precision-targeted therapy in those patients.
Abstract 15194: Nitrative Modification of Caveolin-3, a Novel Mechanism Revealing Cardiac Insulin Resistance in Ischemic Heart Failure
Authors: Yajing Wang, Zhijun Meng, Jianli Zhao, Peng Yao, Ling Zhang, Zhen Zhang, Dina Xie, Wayne Bond LAU, Theodore Christopher, Bernard L Lopez, Di Zhu, Demin Liu, Erhe Gao, Harry Ischiropoulos, Walter J Koch, Xinliang L Ma
Journal: Circulation (2022)

Introduction: Myocardial insulin resistant is a hallmark of diabetic cardiac injury. However, underlying molecular mechanisms remain unclear. Recent studies show that diabetic heart is resistant to other cardioprotective interventions, including adiponectin and pre-conditioning. The “universal” resistance to multiple therapeutic interventions suggests impairment of the requisite molecule(s) involved in broad pro-survival signaling cascades. Caveolin (Cav) is a scaffolding protein coordinating transmembrane signaling transduction. However, role of Cav3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure (HF) is unknown. Methods and Results: Mice were fed normal diet (ND) or high-fat-diet (HFD) and subjected to myocardial ischemia and reperfusion. The cardioprotective effect of insulin was significantly blunted as early as 4 weeks of HFD feeding (pre-diabetes), when insulin signals remain unchanged. However, Cav3/IRβ complex formation, requisite for insulin transmembrane signaling, was significantly reduced. Among multiple post-translational modifications altering proteins interaction, Cav3 (not IRβ or AdipoR1) tyrosine nitration is prominent in the pre-diabetic heart. SIN-1 treatment reduced the signalsome formation and blocked insulin transmembrane signaling. Mass spectrometry identified Tyr 73 is the Cav3 nitration site. Phenylalanine substitution of Tyr 73 (Cav3 Y73F ) abolished SIN-1 induced Cav3 nitration, restored Cav3/IRβ complex, and rescued insulin transmembrane signaling. AAV9-mediated cardiac Cav3 Y73F re-expression blocked HFD-induced Cav3 nitration, preserved Cav3 signalsome integrity, and rescued insulin protective action against ischemic HF. Finally, diabetic nitrative modification of Cav3 at Tyr 73 also reduced Cav3/AdipoR1 complex formation and blocked adiponectin cardioprotective signaling. Conclusion: Nitration of Cav3 at Tyr 73 and resultant signal complex dissociation is responsible for cardiac insulin/adiponectin resistance in the pre-diabetic heart, contributing to ischemic HF progression. Early interventions preserving Cav3-centered signalsome integrity is an effective novel strategy against diabetic exacerbation of ischemic HF.
Abstract 15054: Genome Wide Association Study of Coronary Microvascular Disease Assessed by Cardiac Perfusion Positron Emission Tomography
Authors: Shefali Verma, Lindsay Guare, Brett Irving, Michael Levin, Marie A Guerraty
Journal: Circulation (2022)

Introduction: Coronary Microvascular Disease (CMVD), defined as disease of the coronary pre-arterioles, arterioles, and capillaries, accounts for 30-50% of the burden of ischemic heart disease. However, little is known about the pathogenesis, and there are no directed therapies for CMVD. Perfusion cardiac PET allows for the quantitative assessment of myocardial blood flow (MBF) at rest and stress and MBF reserve (MBFR) and represents the most clinical advanced non-invasive imaging modality for CMVD. Hypothesis: Here we perform the first genome-wide association study (GWAS) for CMVD using cardiac PET MBF parameters. Methods: Rest and stress MBF and MBFR were measured using Rubidium-82 cardiac perfusion PET stress tests which were obtained as part of routine clinical care. We performed a GWAS in 383 samples of European (EUR) and 539 samples of African ancestry (AFR) in the Penn Medicine Biobank using MBF values and REGENIE software. Models were adjusted for age, sex, age 2 , age x sex, 5 principal components, and batch corresponding to phenotype extraction. Additionally fine mapping was performed for loci with P-value &lt; 1e-05 using implementation of SuSiE in the polyfun package by integrating gene expression and functional annotations from heart ventricular, atrium, aorta, and coronary artery tissues in the EpiMap database. Results: We identified 10 variants in AFR ancestry for MBFR at p-value &lt; 5e-7. Among the top hits, our results identified novel signals in variants mapping to LOC105374051, UNC13A, RPL21P130, ATP6V0A2, CCSER1, and MDFI , among others. We also identified 4 variants in AFR and 1 in EUR for rest MBF and 3 variants in AFR and 1 in EUR for stress MBF phenotypes, including loci near ARHGAP18 and ARHGAP22 . Fine mapping identified 4 loci in AFR for MBFR including NRP1, ERC1, RN7SKP148, and SCL15A4 . In sex-stratified analyses, we found that variants were more strongly associated with PET-derived MBF phenotypes in AFR women than in AFR men and in EUR men relative to EUR women. Conclusions: Our study identified several variants associated with perfusion PET MBF parameters in populations of EUR and AFR ancestry, some of which represent putative CMVD loci. This work yields novel insights into mechanisms of CMVD.
Abstract 14569: Impact of Psoriasis on Inpatient Outcomes of Patients Admitted for Coronary Artery Bypass Graft: Analysis of the National Inpatient Sample
Authors: Sania Saleem, Ayesha Abbasi, Sami Shoura, Emmanuel Akuna, Mahak K Bhatti, Sandhya-Shri Kannayiram
Journal: Circulation (2022)

Introduction: Psoriasis is a systemic chronic inflammatory disorder with a global prevalence of 2-3%. Characterized by its skin manifestations and multiple comorbidities, it is notably associated with 50% increased likelihood of coronary artery, cerebrovascular and peripheral artery diseases. This study aims to assess the impact of psoriasis on inpatient outcomes of patients admitted for coronary artery bypass graft (CABG). Hypothesis: Co-existing psoriasis worsens hospital outcomes in patients admitted for CABG. Methods: We searched the National Inpatient Sample (NIS) 2016-17 database to identify adult hospitalizations with CABG as the principal diagnosis with and without psoriasis as a secondary diagnosis using ICD-10 codes. The primary outcome was inpatient mortality. Secondary outcomes were length of hospital stay (LOS) and total hospital charge (THC). Using Stata 17 software, multivariable logistic and linear regression analysis were applied to adjust for confounders. Results: There were over 71 million discharges included in the combined 2016-17 NIS database. Out of 477,389 CABG hospitalizations, 3,765 (0.8%) had psoriasis. The adjusted odds ratio (AOR) for inpatient mortality for CABG with co-existing psoriasis compared to those without psoriasis was 0.67 (95% CI 0.39-1.15, p=0.146). Hospitalizations for CABG with co-existing psoriasis had a decreased adjusted mean LOS by -0.44 days (95% CI {-0.85} - {-0.25}, p=0.037) and incurred a lower THC by -16,178.83 USD (95% CI {-27,541.02} - {4,816.63}, P=0.005) compared to those without psoriasis. Conclusions: In summary our study showed that CABG patients with psoriasis had a lower THC and LOS with no significant difference in mortality compared to CABG patients without psoriasis. It may be attributed to younger age group or immunosuppressive therapy and might warrant investigation into a more lenient CABG criteria for psoriasis patients.
Abstract 15192: Neighborhood Social Vulnerability Predicts Cardiovascular Disease Outcomes Through Pro-Inflammatory Risk Factors
Authors: Zakaria Almuwaqqat, Aditi Nayak, Mohamed Afif Martini, Shabatun Islam, Kiran Ejaz, Zahran Alras, Ayman A Alkhoder, Anurag Mehta, Yi-An Ko, Laurence Sperling, Arshed A Quyyumi
Journal: Circulation (2022)

Introduction: Emerging evidence suggests that neighborhood adverse characteristics are linked to nationwide disparities in cardiovascular disease (CVD) incidence and mortality. However, it is unclear if this association is linked to disease progression and outcomes in people with established CVD. Hypothesis: We hypothesized that in patients with CVD, neighborhood social adversity, measured as social vulnerability index (SVI) predicts incident cardiovascular events at least partly through pro-inflammatory. Methods: A total of 4150 participants enrolled in the Emory Cardiovascular Biobank, residential addresses were geocoded according to the census tract and SVI was determined using the Center for Disease Control data. Serum hs-C-reactive protein (hsCRP) levels were measured during enrollment and participants were followed up for incident myocardial infarction (MI) and cardiovascular death. Subdistribution hazard models were used to investigate the association between SVI and the study endpoint. A mediation analysis was performed to evaluate whether hsCRP levels underly this association. Results: Mean age was 63 years, 24% Black, and 64% were women. During a median 5 year follow-up, there were 904 (22%) adverse events. SVI and hsCRP were correlated (r=0.12, P&lt;0.001). After adjustment for age, race, sex,hypertension, diabetes mellitus, body mass index, prior MI, prior heart failure, renal function, smoking, statin and aspirin use, participants in the highest SVI quartile (most socially vulnerable), had a 31% (95%CI, 4%,64%) higher risk of CV death/MI compared to those in the lowest quartile. The risk was attenuated and became insignificant after adjusting for the hsCRP 23% (CI -3%, 54%). Serum hsCRP levels mediated 61% of the association between SVI and adverse events. Conclusions: Neighborhood social vulnerability is an independent risk factor for adverse outcomes in CVD, that is at least in part mediated through increased systemic inflammation. Neighborhood social vulnerability may explain some of the residual risk observed in patients with CVD.
Abstract 15189: The <i>‘July Effect’</i> in the Management and Outcomes of Acute Myocardial Infarction: An 18-Year United States National Study
Authors: Sri H Patlolla, Saraschandra Vallabhajosyula
Journal: Circulation (2022)

Introduction: Limited clinical experience of new trainees has been associated with poor outcomes in the first month of training (July) in teaching hospitals. It remains unclear if this ‘July effect’ continues to be present in contemporary era in patients with acute myocardial infarction (AMI). Methods: Adult hospitalizations for AMI in May and July in urban teaching and non-teaching hospitals in the United States were identified from the HCUP-NIS database (2000-2017). Admissions to rural hospitals, and those without in-hospital mortality data were excluded. In-hospital mortality was compared between those admitted in May and July. A difference-in-difference analysis comparing a change in outcome from May to July in teaching hospitals to a change in outcome from May to July in non-teaching hospitals was also performed to evaluate the July effect. Results: During the study period, there were a total of 1,312,006 hospitalizations for AMI admitted in urban teaching (54.2%) or non-teaching (45.8%) hospitals in the months of May and July. Demographic characteristics were comparable between those admitted in May and July, however, May admissions had greater comorbidity and higher rates of acute multiorgan failure when compared to July admissions in teaching and non-teaching hospitals. Additionally, May AMI admissions to non-teaching hospitals had higher rates of cardiogenic shock (4.6% vs 4.3%) and cardiac arrest (5.2% vs 5.0%) compared to July admissions ( all p&lt;0.001). July AMI admissions had lower in-hospital mortality compared to May admissions in both teaching (5.6% vs 5.8%; adjusted OR (aOR) 0.94 [95% confidence interval {CI} 0.92-0.97]; p&lt;0.001) and non-teaching (5.9% vs 6.3%, p&lt;0.001; aOR 0.97 [95% CI 0.95-0.99]; p=0.02) hospitals. When we analyzed the July effect using the difference-in-difference model for in-hospital mortality, we did not identify a July effect for in-hospital mortality in AMI admissions (p=0.14). Conclusions: Unlike prior reports, we did not identify a July effect for in-hospital mortality in this large contemporary AMI population in the United States. Greater care and support for new incoming trainees and/or awareness of a potential July effect among hospitals may have resulted in improved outcomes in July when compared to May.
Abstract 14702: The Burden of Cardiac Adverse Events Associated With Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: A Large Pharmacovigilance Database Analysis
Authors: Anuj Thakre, Akhilesh Babbili, Sahith Reddy Thotamgari, Udhayvir Grewal, Kavitha Beedupalli, Paari Dominic
Journal: Circulation (2022)

Introduction: Anaplastic Lymphoma Kinase tyrosine kinase inhibitors (ALK TKIs) have played a pivotal role in the management of Metastatic Non-Small-Cell Lung Cancer (NSCLC). ALK rearrangements are associated with improved survival compared to the standard first-line therapy. However, the cardiovascular safety profile of these agents remains understudied. Methods: We interrogated the Food and Drug Administration’s Adverse Event Reporting System (FAERS) database for the reported cardiac adverse events (AE) of: crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. The number of cardiac AEs reported for ALK TKIs were compared with all the other drugs between 2011-2022. Disproportionality analysis was performed using Reporting Odds Ratio (ROR). Results: We identified a total of 20,337 AEs for ALK TKIs, of which 1191 were cardiac AEs. The most frequently reported cardiac AEs associated with ALK TKIs were pericardial diseases (271), followed by bradyarrhythmia (253) and heart failure (HF) (245). HF reporting was significantly higher with lorlatinib (ROR 2.9; CI 95% 2.0-4.1). Ceretinib was associated with significantly higher reporting of pericardial diseases (ROR 28.3; CI 95% 22.6-35.3), and other tachyarrhythmias (ROR 8.9; CI 95% 5.7-13.8). Alectinib was associated with significantly higher reporting of bradyarrhythmias (ROR 9.7, CI 95% 7.8-12.1). Conclusion: Cardiovascular AEs were disproportionately higher with ALK TKIs for pericardial diseases and bradyarrhythmias with ceretinib and alectinib respectively. Larger prospective studies are needed to identify high-risk groups that would benefit from robust cardiovascular surveillance.
Abstract 15247: A Novel Patient-Derived Stem Cell Model of Restrictive Cardiomyopathy Exhibits Impaired Cardiomyocyte Relaxation Secondary to Increased Myocardial Calcium Sensitivity
Authors: David Staudt, Ricardo Serrano, Dries Feyen, Mark Mercola
Journal: Circulation (2022)

Introduction: Restrictive Cardiomyopathy (RCM) is a rare disease characterized by profound, isolated defects in myocardial relaxation, normal or near-normal myocardial wall thickness, and preserved contractile function. Outcomes for patients with RCM are poor, with increased morbidity and mortality compared to other forms of cardiomyopathy. In some patients, RCM can be caused by genetic mutations, notably in genes encoding for components of the sarcomere. While many mutations have been described in RCM patients, the molecular and cellular mechanisms leading from these mutations to the patient’s physiological phenotype are poorly described. Hypothesis: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) derived from RCM patients will recapitulate the myocardial relaxation defects seen in RCM and provide a novel in vitro model for investigating the molecular mechanisms underpinning this disease. Methods: Induced pluripotent stem cells (iPSCs) were derived from a pediatric patient with RCM caused by a TNNT2 R94C mutation. CRISPR was used to correct the mutation, and cellular mechanics and calcium handling properties were compared to the patient line using a novel high-throughput traction-force imaging platform. Transcriptional profiles were compared using RNA-seq. Results: RCM cells carrying the TNNT2 R94C mutation show increased calcium sensitivity leading to increased resting tension at baseline, as well as prolonged calcium kinetics leading to prolonged relaxation times. Gene expression profiling reveals changes in expression of ECM genes, which may further contribute to the impaired myocardial relaxation seen in RCM. Conclusions: Patient-derived hiPSC-CMs from an RCM patient recapitulate the relaxation defects seen in RCM and highlight the central role of increased calcium sensitivity in impaired myocardial relaxation.
Abstract 15020: Activation of Mitochondrial Bk <sub>Ca</sub> Channels Improves Hemodynamics and Normalizes Phosphoproteomic Changes in Pigs Following Cardioplegic Arrest and Cardiopulmonary Bypass
Authors: Wenzhuo Ma, Neel Sodha, Martin Kolodziejczak, Zhiqi Zhang, Scarlett Huck, Ahmed Aboulgheit, Clarissa Muller, frank sellke, Jun Feng, Dmitry Terentyev, Richard T Clements
Journal: Circulation (2022)

Introduction: BKCa channels are large conductance Ca++-activated K+ channels, which reside in the inner mitochondrial membrane in cardiomyocytes. We have demonstrated that the BKCa channel activator rottlerin (a.k.a mallotoxin) is cardioprotective during cardioplegic arrest in isolated rodent hearts and in vitro models. Here we used a clinically relevant in vivo swine model of cardioplegic arrest and cardiopulmonary bypass (CP/CPB) with and without rottlerin supplemented CP solution. Mitochondrial signaling alterations were identified by TMT-MS analysis of phosphorylation enriched mitochondrial protein fractions. Methods: Yorkshire swine (50 Kg) of both sexes were subjected to hypothermic CP/CPB (1hour) followed by 1 hour reperfusion. Groups included sham (n = 5), CP/CPB alone (n = 8) and CP/CPB with rottlerin supplemented cardioplegia (1uM) (CP/CPB+R) (n = 7). Mitochondria-enriched fractions were isolated from the left ventricular free wall and subjected to Tandem Mass Tag (TMT) labeling coupled mass spectrometry analysis. Results: CP/CPB pigs had reduced myocardial function indicative of myocardial stunning as shown by decreased LVDevP, and ±dP/dt vs sham (P&lt;.05). BKCa activation significantly restored left ventricular function compared to CP/CPB alone (LVDevP: 74.0 ± 2.8 vs . 52.5±5.0 mmHg, P &lt; .01, +dP/dt: 1482±116 vs . 923±126 mmHg/s, P &lt; .01, and - dP/dt: 1120±116 vs . 629±82 mmHg/s, P &lt; .01). TMT-MS analysis identified 3363 proteins. 410 unique as well as numerous novel phosphorylation sites were significantly regulated in CP/CPB vs sham. Rottlerin treatment generally normalized phosphorylation changes with 175 and 63 different vs CP/CPB and sham, respectively. Enrichment analysis demonstrated significant changes in pathways associated with adrenergic and PKA signaling, calcium handling, mitochondrial dynamics, cristae organization, and oxidative phosphorylation. Conclusions: BKCa-activator supplemented cardioplegia significantly improves myocardial functional recovery following CP/CPB in a clinically relevant large animal model. Furthermore, mitochondrial BKCa-channel activation during cardioplegic arrest normalizes numerous signaling alterations associated with myocardial stunning and cardiac surgery.
Abstract 15834: Joint Associations Between Resting Heart Rate and Blood Pressure on All-Cause Mortality
Authors: Trishna Parikh, Sumaiya Islam, Moizz Akhtar, Fariha Hameed, Bharath Nagaraj, Aayush Visaria
Journal: Circulation (2022)

Introduction: Both blood pressure and heart rate (HR) are important factors that constitute hemodynamic status. Hypothesis: We aimed to determine whether HR was independently associated with all-cause mortality and whether HR modified the association between systolic blood pressure (SBP) and all-cause mortality. Methods: We included adults aged ≥20 years from the 1999-2018 National Health and Nutrition Examination Surveys without cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, cancer, asthma, or beta blocker use. Resting HR was categorized into 10 beats-per-min increments, and SBP in 10-20 mmHg increments as shown in Table 1. Our primary outcome was all-cause mortality, determined using linkage to the National Death Index through 2019. We used multivariable Cox regression, stratified by HTN status and adjusted for the survey design. Results: Among 27,369 participants, 5984 (22%) had diagnosed HTN. A HR ≥80 was associated with at least a 30% increase in mortality risk, regardless of HTN status (Table 1). Among normotensive participants, a HR ≥80 was associated with higher mortality risk compared to HR &lt;80 at all SBPs except for SBP ≥180 (Table 1). While there was significant interaction between continuous HR and SBP on all-cause mortality (p=0.02), there was no evidence of significant effect modification within individual SBP categories. Conclusions: A HR ≥80 was independently associated with increased all-cause mortality risk, regardless of HTN diagnosis. HR may be a surrogate for cardiorespiratory fitness. Further studies understanding the joint associations between SBP and HR are needed in both normotensive and hypertensive individuals.